Physical Activity Reduces Return to Cocaine Seeking in Animal Tests

Aerobic exercise might help cocaine abusers establish and maintain abstinence, recent NIDA-funded animal research suggests. In two independent studies, running on an exercise wheel reduced rats’ cocaine seeking during
forced abstinence
and their eagerness to resume cocaine seeking following the abstinence. One study indicated that exercise may produce these effects in part by lowering brain levels of a protein that has been linked to drug craving.

The research teams, one led by Dr. Marilyn Carroll at the University of Minnesota and the other by Dr. Wendy Lynch at the University of Virginia, examined the impact of exercise on drug seeking with a protocol that researchers often use to test potential addiction medications. Their work highlights the potential usefulness of such protocols for assessing behavioral approaches to addiction treatment as well.

Exercise

The research teams varied details of the test protocol, but both preserved its basic three-phase structure, which parallels a person’s acquisition of chronic drug abuse, establishment of abstinence, and exposure to a relapse trigger:

Self-administration: The animal self-administers cocaine infusions by pressing a lever, ultimately leveling off at a dosage that it apparently finds optimal.

Extinction (of the lever-pressing behavior): The researchers deactivate the lever and observe how rapidly the rat tapers off its lever pressing in the absence of the drug reward.

Reinstatement: The researchers expose the rat to some strong reminder of the rewarding sensations produced by the drug—e.g., a priming dose or drug-associated cues—and observe how avidly the animal resumes lever pressing.

In studies with this protocol, researchers administer a potential treatment after the self-administration phase and judge it to be effective if it results in reduced lever pressing during extinction and/or reinstatement. Hence, the Virginia and Minnesota teams moved their animals to cages with exercise wheels after the self-administration stage (see chart).Both found that animals that ran on the wheels tapered off lever pressing faster during extinction and took it up less avidly during reinstatement, compared with control animals placed in cages with locked running wheels.

The Experimental Protocols Using slightly different procedures, each team combined standard drug self-administration and reinstatement procedures—an
animal model
of relapse—with access to a running wheel to investigate whether exercise reduces cocaine seeking.

In the Minnesota study, female rats that exercised pressed the lever about half as often, on average, during the first 9 days of the 14-day extinction phase. Dr. Carroll and colleagues also found that exercise reduced lever pressing during reinstatement when animals ran on the same day that they received a priming dose of cocaine, but not when there was a delay between receiving the priming dose and being introduced to the wheel.

In the Virginia study, male rats that exercised for up to 2 hours a day during a 2-week period of forced abstinence between self-administration and extinction pressed the lever about 35 percent less often during the extinction phase and about 45 percent less often during reinstatement.

Decreased Neuroadaptation

Both studies indicate that exercise does more than simply provide an alternative activity that reduces the time available for drug seeking, the researchers say. The researchers note that both exercise and addictive drugs raise levels of dopamine in the brain’s reward system, and as a result, exercise may compete with cocaine as a source of pleasurable sensations. In addition, the Virginia researchers found evidence suggesting that exercise may alter levels of the neurotransmitter glutamate in their rats’ prefrontal cortex (PFC). Such an effect might weaken the progressive intensification (incubation) of craving that takes place during early abstinence from cocaine and appears to depend largely on glutamate.

Dr. Lynch and colleagues assayed brain tissue from the PFC of their animals 1 day after the end of reinstatement. Exercise was associated with 32- and 42-percent reductions in the activity of two proteins, extracellular signal-regulated kinase (ERK) 1 and 2, whose levels are regulated by both dopamine and glutamate. Previous research has established associations between ERK,
drug-seeking behavior
, and the incubation of cocaine craving.

Activity Reduces Rats’ Return to Cocaine In a study at the University of Minnesota, female rats that had access to a functional running wheel during extinction pressed the cocaine-delivery lever less often during this period than rats that did not have such access (left-hand graph). In response to a priming injection of the drug, rats that had access to a running wheel during reinstatement pressed the cocaine-delivery lever less often at this stage than rats with a locked wheel or access to a running wheel only during extinction (right-hand graph).